Plasticity in MS: from functional imaging to rehabilitation.
Abstract: One of the main characteristics of multiple sclerosis (MS) is the existence of a 'clinico-radiological paradox'. The discrepancies observed between the clinical and radiological findings might be partly attributable to lack of specificity of the imaging measures, but also to functional reorganization mechanisms occurring at both the brain and spinal cord levels. These neuroplastic processes might provide a means of delaying the clinical expression of some functional symptoms. Functional MRI (fMRI) methods provide a useful means of determining whether functional reorganization mechanisms of this kind are at work. It has been established, for example, that these neuroplastic mechanisms occur right from the start of the disease and may contribute to reducing the expression of the symptoms resulting from pathological tissue damage. This functional reorganization may therefore constitute an important adaptive mechanism during the early stages of the disease. One potential practical application of the findings made on these neuroplastic processes is likely to be the development of specific rehabilitation methods, which can be used to enhance these reactive mechanisms in order to maintain MS patients' functional abilities, and other specifically targeted approaches will also predictably be developed.

Article Type: Report
Subject: Multiple sclerosis (Development and progression)
Multiple sclerosis (Diagnosis)
Neuroplasticity (Health aspects)
Magnetic resonance imaging (Usage)
Physical therapy (Research)
Therapeutics, Physiological (Research)
Authors: Pelletier, J.
Audoin, B.
Reuter, F.
Ranjeva, J.P.
Pub Date: 03/01/2009
Publication: Name: The International MS Journal Publisher: PAREXEL MMS Europe Ltd. Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2009 PAREXEL MMS Europe Ltd. ISSN: 1352-8963
Issue: Date: March, 2009 Source Volume: 16 Source Issue: 1
Topic: Event Code: 310 Science & research
Geographic: Geographic Scope: France Geographic Code: 4EUFR France
Accession Number: 217847855
Full Text: Introduction

Multiple sclerosis (MS) is characterized by the fact that although the evolution of the disease is often unpredictable, the temporal and spatial dynamics play a particularly important role. The so-called 'clinico-radiological paradox' whereby the pathological lesions are associated with only weak clinical symptoms although considerable changes are detected at MRI level, might be attributable to various factors inherent to the disease, such as the fact that some of the lesions located in non-functional territories are 'silent', the occurrence of spontaneous repair and/or remyelination processes in patients with inflammatory lesions, and/or ion channel redistribution mechanisms.

The lack of specificity of the imaging measures, and in particular, the pathological heterogeneity of T2-visible MRI lesions, could also be in part an explanation for the MS clinico-radiological paradox. In addition, the existence of neuroplastic mechanisms reflecting the plasticity of the adult human brain has been amply documented during the past few years. This functional brain plasticity may be mediated by various processes, such as cell renewal, remyelination, neurite extension, new synapse formation, ion channel redistribution and cortical reorganization processes involving the main associative pathways. The neuroplastic processes occurring in response to pathological lesions may reduce the functional consequences of these lesions and thus prevent or reduce the clinical expression of the symptoms. It was recently suggested, on the basis of fMRI studies, that cortical reorganization processes of this kind might prevent the expression of acute symptoms (relapses) and slow down the gradual aggravation of the natural evolution of the disease.

fMRI Studies on MS

The processes observed using fMRI methods result from local variations in the cerebral blood oxygen levels and blood flow triggered by the activation of the cortical regions associated with the performance of specific tasks. Haemoglobin, the magnetic properties of which depend on its oxidation state, constitutes a useful endogenous contrast product. In the cortical regions activated, the partial oxygen blood pressure decreases the deoxyhaemoglobin levels, thus reducing the local magnetic field measured using MRI methods, which makes it possible to detect any changes in the signals occurring in the zones involved (this is the BOLD effect: the Blood Oxygen Level Dependent contrast effect). The changes in cortical activity resulting from the performance of a motor, cognitive or visual task can be detected by comparing the difference between the signal observed on MRI during the activation phase and the resting phase (which is known as the blocked mode). Statistical analyses can be carried out in order to determine the cortical regions where the signal differs significantly between the resting and activation phases, and the statistical map thus obtained can be superimposed on an anatomical image in order to determine exactly which regions have been activated.

fMRI methods therefore undeniably constitute a valuable means of studying the functional brain reorganization occurring secondary to MS lesions: this method makes it possible to establish correlations between the extent of pathological processes and the corresponding patterns of brain activation, and thus to assess the functional benefits of this cerebral plasticity.

fMRI and Plasticity in MS fMRI and Motor and Sensory Tasks

Several authors have shown that the regions activated in patients with remittent or primary progressive forms of MS performing motor tasks were the classical motor regions as well as multimodal cortical regions which are normally not activated during the performance of tasks of this kind. (1,2) This finding suggests that the mechanisms responsible for functional reorganization involve not only the recruitment of vicarious motor circuits, but also more complex processes. In particular, it was recently reported that functional cortical reorganization processes occurred during the initial stage of the disease (clinically isolated syndrome [CIS]), since a greater and more diffuse level of activation occurred in patients than in the control subjects in both the contra- and ipsilateral motor cortex, although both populations achieved similar motor performances. (3) At this stage of the disease, the plasticity of the brain may therefore contribute to maintaining normal motor performances despite the presence of tissue lesions. These findings clearly suggest that a compensatory process intervenes at an early stage of the disease in the patients' motor system. (4) The patterns of activation detected in the cortical regions of patients but not in control subjects during the performance of simple motor tasks may have resulted from the fact that brain networks normally mediating more complex motor tasks were recruited. (5) One of the main principles underlying the compensatory reorganization processes occurring in patients with pathological lesions and enabling them to perform simple tasks as efficiently as normal subjects may therefore involve the recruitment of brain systems normally devoted to complex activities. This hypothesis would at least partly account for the feeling expressed by the patients tested that considerable mental efforts were required to perform a simple task. Similar findings have been made on CIS patients, in whom networks normally involved in the performance of complex motor tasks were recruited while simpler tasks were being performed. These findings suggest that neuroplastic mechanisms occurring in the very early stages of the disease may prevent or delay the clinical expression of the patients' motor impairments. This functional reorganization may vary, depending on the clinical form of the disease and its time course. These neuroplastic processes might be particularly effective in young patients with only slight disabilities and weak diffuse structural damage, and became weaker with the extent of the disabilities and the aggravation of the structural diffuse changes. (7,8) The functional reorganization detected using fMRI methods does not actually seem to be restricted to the brain, since authors using this method recently observed changes in the patterns of activation recorded in the cervical medulla in response to proprioceptive stimulation, which might also contribute to reducing the clinical consequences of pathological tissue lesions. (9,10)

fMRI and Cognitive Tasks

The question of whether cerebral plasticity, which may reduce the clinical repercussions of pathological processes in the case of motor activities, might also apply to more complex functions has been raised. Recent studies on brain network reorganization during the performance of complex cognitive tasks have shown that the patterns of cortical activation recorded in the prefrontal and parietal regions and the anterior cingulate cortex differed from those recorded in the control group. (11-13) The various patterns of cortical activation recorded suggest the occurrence of complex processes of reorganization involving both the working memory and brain regions which are not normally recruited during the performance of tasks of this kind. The authors of recent studies using PASAT procedures on patients in the early stage of CIS established that compensatory functional cortical processes contributed to complex information processing operations in these patients. (14,15) Changes in cortical activation patterns have also been observed in patients whose performances did not differ from those of control subjects. The changes observed are both quantitative (greater levels of activation have been recorded in the right and left prefrontal cortices of patients than in control subjects) and topographic (the right fronto-polar cortex and the right cerebellar hemisphere were found to be involved) (Figure 1). Some more specific studies have also been performed using effective and functional connectivity methods to detect changes in the functional connections between various cortical regions involved in complex information processing. The results obtained have shown a functional connectivity decrease and a modulation of effective connectivity between the cortical areas involved in the working memory system. (16,17) These processes of reorganization may therefore play a compensatory role by reducing the cognitive effects of the pathological processes, thus considerably masking the functional repercussions of the tissue lesions occurring in the early stages of the disease. Several factors might contribute to the existence and the extent of these adaptive functional mechanisms. First of all, the presence of severe cognitive deficits predominating at the attentional level might be a factor inhibiting neuroplasticity. (18) Secondly, the compensatory mechanisms might depend on the clinical form of the disease. (19) Last but not least, the patients' level of education (their 'cognitive reserves') might contribute decisively to the development of compensatory functional reorganization processes. (20,21)


Morphological, Structural and Metabolic Correlates of Brain Plasticity in MS

A number of studies have shown the existence of significant correlations between the occurrence of cortical reorganization and the lesion load assessed on T2-weighted sequences. However, the diffuse damage undergone by the cerebral parenchyma (especially in the normal appearing white matter [NAWM]) was found to be a more related to cortical reorganization than the lesion load or the topographical distribution of the lesions. The enhanced recruitment of the cortical regions involved in the performance of motor tasks was found to be significantly associated with diffuse tissue damage, as assessed using magnetization transfer and diffusion imaging methods and based on the decreased levels of N-Acetyl Aspartate (a marker of axonal dysfunction) using MR spectroscopy imaging. (22) Likewise, quantification of the overall tissue damage has made it possible to assess the functional effects of diffuse white matter tissue damage on the functional reorganization mechanisms occurring in the earliest stage of the disease, using methods based on cognitive tasks (Figure 2). (23,24) Interestingly, using perfusion MRI, recent studies have shown a decreased perfusion of the NAWM that might be caused by a widespread astrocyte dysfunction. (25) Early diffuse brain damage might therefore trigger these recruited functional reorganization processes preventing the clinical expression of the symptoms of the disease. (26) MS may also involve functional changes in the connections involved in the activation of the cortical regions associated with the motor and cognitive abilities tested. (15,16,27,28) Lastly, this functional plasticity might be partly mediated by structural changes in the associative pathways involved in the functional reorganization processes, since it was recently reported by authors using a diffusion tensor tractography imaging approach that the number of connections between some brain regions was higher in MS patients than in control subjects, which suggests that the white matter was endowed with reactive structural plasticity. (29)



The finding that neuroplastic processes may reduce the clinical expression of some symptoms, such as motor disorders and cognitive deficits, during the early stages of MS should make it possible in the near future to develop rehabilitation strategies based on specific training designed to enhance these potential compensatory mechanisms and thus to maintain the patients' functional performances by preventing or reducing the clinical expression of the disease. (30,31) In addition, the functional reorganization processes recently found to occur suggest that a targeted therapeutic approach could be developed to deal with these symptoms, on similar lines to what has been done in the framework of some cognitive disturbances. (32) Further information is still required, however, about the mechanisms underlying this functional reorganization and their morphological, structural and metabolic correlates. For this purpose, longitudinal studies will have to be carried out to determine how these compensatory processes evolve with time, and to establish in particular what the limiting factors may be, such as the thresholds beyond which these processes may no longer be effective (Figure 3). (33,34) Despite technical problems affecting fMRI data acquisition and analysis which still remain to be solved, multicentre studies on the use of this approach should definitely be envisaged. (35)


Key Points

* fMRI studies have recently established that neuroplastic processes occur in patients with MS

* These compensatory functional reorganization processes, which have been found to occur in the very earliest stages of the disease, may limit the clinical expression of some of the symptoms of the disease

* The diffuse structural and metabolic damage detected using non-conventional MRI methods have been found to contribute more decisively to explain these neuroplastic processes than the topographic distribution of the macroscopically identified lesions or the extent of these lesions

* In the early stages of the disease, these compensatory mechanisms may largely mask the functional effects of tissue lesions, which are often fairly slight at this stage, but as the symptoms evolve, neuroplastic mechanisms may no longer suffice to compensate for the increasingly severe structural lesions, and the functional symptoms therefore begin to show up

* Longitudinal studies would help to explain why these compensatory functional processes are liable to be limited, as well as providing information which could be used to develop specific rehabilitation methods for enhancing these reorganizational processes and thus delaying the onset of the functional symptoms in patients with early MS

Received :25 July 2008

Accepted : 14 October 2008


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J Pelletier [1,2], B Audoin [1,2], F Reuter [1,2], JP Ranjeva [2]

[1] Pole de Neurosciences Cliniques, Service de Neurologie

[2] Centre de Resonance Magnetique Biologique et Medicale (CRMBM)-CNRS6612 CHU Timone,Marseille, France

Address for Correspondence

Jean Pelletier

Pole de Neurosciences Cliniques, Service de Neurologie, CRMBM CNRS6612, CHU Timone, Rue Saint Pierre,

13385 Marseille cedex 5, France.

Phone: + 33 (0) 4913 85939

Fax: + 33 (0) 4913 86256

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